Three major receptor subtypes mediate GABAergic inhibitory effects in the mammalian CNS, the GABA-A and GABA-C receptors that generate fast inhibition, and the metabotropic GABA-B receptors (GBR1, GBR2) which mediate slow inhibitory effects via activation of an intracellular second messengers cascade. Data from our laboratory showed that GBR1 receptors are strongly expressed pre- and postsynaptically throughout the monkey basal ganglia. Interestingly, pre-synaptic GBR1 immunoreactivity is mainly associated with glutamatergic terminals suggesting that GABA-B receptors act as heteroreceptors that modulate glutamate release in these structures. To further elucidate the roles of GABA-B receptors in basal ganglia, we propose a series of anatomical, neurochemical and behavioral studies to characterize various aspects of GABA-B receptor localization and functions in the globus pallidus (GP) and subthalamic nucleus (STN) of normal and parkinsonian monkeys. It is well established that overactivity of glutamatergic pathways from the STN to basal ganglia output structures, namely the internal segment of the globus pallidus (GPi) and the substantia nigra pars reticulata (SNr), is a cardinal feature of the pathophysiology of Parkinson's disease (PD). Our preliminary data raise the interesting possibility that activation of presynaptic GABA-B receptors in GP and STN may reduce transmission at overactive subthalamofugal synapses. In this model, activation of GABA-B receptors would attenuate some of the parkinsonian motor symptoms. In support of this notion, our data also indicate that local administration of GABA-B receptor agonists in GPi and STN reduces glutamate release in primates and that systemic application of these compounds may have beneficial therapeutic effects in parkinsonian monkeys. The following four specific aims are proposed: (1) Characterize and compare the pattern of subcellular and subsynaptic localization of GABA-B Ri immunoreactivity in the GP and STh of normal and parkinsonian monkeys, (2) Determine the exact source of glutamatergic axon terminals that express pre-synaptic GABA-B receptors in GP and STN, (3) Test the possibility that local application of GABA-B agonists decreases glutamate levels in the GP and STN of normal monkeys and (4) Test the potential therapeutic effects of GABA-B receptor agonists in parkinsonian monkeys. These experiments will further delineate the subsynaptic localization and roles of GABA-B receptors in modulating glutamate release and open novel research avenues for the potential use of GABA-B agonists in the pharmacotherapy of PD.
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